2-substituted-3, 4-diamino-furan urethans and derivatives thereof



general Formula I.

Patented Nov. 9, 1948 UNITED STATES PATENTOFFICE 2 siies'rrrp'rsn 3,4 DIAMINO -FURAN UnE'rriANs AND DERIVATIVES THEREOF Klaus Hofinann, Pittsburgh, Pa assignor to Ciba Pharmaceutical Products, Incorporated, Sum mit, N. 3., a corporation of New Jersey 1 No Drawin Application March-27, 1945; Serial No. 585,193

10 Claims. (Cl. 260345) The present application is impart a continuation of copend ng application, Serial No. 511,610, filed on November 24, 1943 (U. S. Pat. No. 2,432,- 016), which is itself in part a continuation of copending application, Serial No. 459,674, filed on September 25, 1942 (Us. Pat. No. 2,382,418) and the invention to which the presentappllication relates is a further development of the inventions described and claimed in said copending applica M tions. The present invention relates to a process of preparing "2-substituted BA-diamino-furan urethans and theircorresponding saturated analogs of the general structural or IA:

Hit 1 enewmrm wherein R1 representsa hydrogen atom, a carboxyl group or a group which is convertible to a carboxyl group, and R2 represents an alkyl, aralkyl or arylradical; and to the resultant products.

According to thepresent invention the said furan derivatives are prepared by reacting a 2- substituted furan- BA-dicarboXyliC acid II with a halogenating agent to produce the corresponding diacidhalide III, which thereafter is treated with an alkali metal azide to form the corresponding "lytic hydrogenation into compounds of the general 7 structure IA, The ease with which the substituted urethans are reduced to the corresponding tetrafaot that reductionof 2 substituted furan-SA- dicarboxylic acids to the corresponding tetrahydro l derivatives requires high'pressure and elevated temperatures. The following formulae illustrate the procedure:

The new urethans are intermediates in a syn thetical procedure forthe preparation of biotin I analogs,

tion.

vvhieh isan u1timateobject of the inven- Suitable starting materials are the fi substituted furans of the Formula II wherein R1 stands for a hydrogen atom, a carboxyl group ora group convertible into a carboxylgroup; and a: stands for one ofthe numbers 1-6 inclusive. These starting compounds maybe prepared, for example, according to the disclosure of copending application Serial N0. 459,674 (UQSQ Pat. 2,382,413) by reacting a correspondingly Z substituted furan derivative with an acetylene dicarboxylic fester, catalytically g hydrogeuerating the resultant "complex, distilling the resultant hydrogenated compound to eliminate a molecule of ethylenethereironitand saponiiyingthe resultantester.

hydro compounds is remarkable, considering the The radicalRz in the general Formulae I and IA is an alkyl radicalsuch as methyl, ethyl, iso- Amongthe"groups which canbetransformed to a carboxylgroup the following ones may be 3 hieritioriedi aliphatic and aromatic ester groups such as the methyl, ethyl, propyl, phenyl, benzyl ester groups; aliphatic and aromatic amide groups such as the amide, monoand dimethyl-amide, diethyl amide, piperidide, anilide, and N-methylanilide groups;...the nitrile group; the hydroxyl group ;'the halogenatoms the aldehydegroup and samples and .claims, designates .the relative position of the amino or substituted amino groups at carbon atoms 3 and 4 of the furan or tetrahydrofuran ring, as the'case may be.

The following examples? illustrate methods of carrying out the present invention, but it is to be understood that'the examples are given by way of illustration and not of limitation.

Example! A solution of 5.0 gr of ;3,4-dicarboxy-2-furan pentanol in 20 ccaof idrygpyridine and 12 cc. of acetic anhydride was kept at room temperature over night. The solvents were removed in vacuo,

the residue was"d-issolved in--ethyl acetate, an

the solution was washed with 2 N hydrochloric acid and 10% sodium bicarbonate. The bicarbonate extractswere'acidified to Congo red with concentrated hydrochloric acid and were then extracted withrethylacetate. 1 The. ethyl acetate was,

washed with water,dried.over sodium sulfate, and removed on the steam bath. The resulting crystalline 3,4adicarboxyi Z-furanpentanol-acetate of melting point 102-10310. was purified by recrystallization from benzene.

for one hour to QOKCz-wiith 10 cc. of thionyl chloride. The .excess of". thionyl chloride was evaporated and the resulting acid chloride of 3,4-dicarboxy-2-furanpentanol-acetate was dis- -tilled in .vacuo.

JLA; solution.of11.0 gaofithe above acidchloride gin. 100.00. .of. ether wasstirred ifOIf two hours in anice bath with a solution of 10 g. of sodium -aZidein-ZS cc.-. of water, 20 cc.-. of 40% potassium hydroxide were then added, and stirring wascon .tinuedfor anladditionalihour. The etherlayer .was separated, .dried .over; sodium. sulfate, and the .oi ly.azide which wamobtained on evaporation of .theether-solution was dissolved in :100 cc. of abso- '..lute alcohoLandwas placed in'a round bottomed .flask,.,equipped with agas'inlet tube and awrefiux .condenser. .Theended the reflux condenser was connected to a. calcium: chloride tube,:. and a -.gas

. washing bottle .filled with concentrated sulfuric ,acid, and.aLslowstream-of nitrogen was passed through the. apparatus. The flask-,was. :then heated slowly to 45a50.C.,-. and maintainedaat this temperature..untilthe initial rapid evolution of .nitrogen had almostuceased. The'temperature was then raised-to the-boiling point of-the alcohol,

wand .thesolution was. refluxed for two hours.

The alcohol solution was cooled-t 20 C; and

.30. cc. .of 1 N1 sodium" hydroxide were addedv and u-ithamixturei-was kept .a iroom temperature over night. The alcohol was removed in vacuo and the residue was extracted with ether. The ether solution was washed with 2 N hydrochloric acid and sodium bicarbonate, was dried over sodium sulfate, and the ether was removed on the .steam. bath. Treatment of .the residue with a =inixture of Zparts of 'etherrand one .part of petroleum ether (30-60 C.) gave the desired 3,4-

. .diaminocarbethoxy-2-furanpentanol of a melting point of 79-81" C. i

Example 2 .A mixtureoi 5.0g. of 3,4-dicarboxy-2-methylfuran. and cc. of'thionyl chloride was heated .to '70-'80" C. forone hour, and the excess of thionyl chloride was removed in vacuo and distillation'of the residue gave the acid chloride of 8A=dicar-boxy-2-methylfuran.

3.03 g. of the above acid chloride in 330 cc. of ether cold 10% .,..45 Five gramsof-the above compound were heated A solution of was added to an ice cold solution of 38.0 g. of

sodium azide in 90 cc.'of water, and the mixture was. stirred in anice bath for two hours.

The .ether layer was then separated, washed with ice sodium bicarbonate and dried over sodium sulfate. The ether was removed in vacuo at room temperature, and the resulting crystalline .azide was dissolved in 400- cc. of absolutefalcohol and was decomposed in the manner describedin Example 1.

The alcohol was removed in vacuo and they'ellow oil which resulted crystallized when .placed in a refrigeratorover night. Recrystalliza- .tion from methanol at 20 C'. gave.the.desired .3,4-diaminocarbethoxy 2-methylfuran .of a. melting point of '105.107'C.

. I Example 3 5.0 g. of the diazide"of;:'3,4-dicarboxy-2-methylfuran (prepared according to Example 2) were dissolved in'"50-cc. of.dry benzene and 4.3 g. of phenol and were decomposed under nitrogen as described in .Example 1. Thesolvents were .removed in vacuo, and the resulting 3,4-diaminocarbophenoxy-Z-methylfuran, melting point 190- 195 C., wasipurifiedflby crystallization from ethyl acetate-methanol.

Example 4 13 15.0 g.. of 3,4-dicarboxy-2efuranbutanolacetate were transformed .into the -corresponding acid chlorideanddiazide as described in Example 1.

. A.solution of .10 gnof .the aforementioned .diazide in 100 cc. of dry. methanol was decomposed under nitrogen.at.45+60.C'.,. as described in. Example 1.

.i .The. methanol .solution was. then cooled to 20 C. .andl cc...of 1.N..sodium.hydroxide-were slowly ....added awhile stirring, and .thesolution was. kept atroom temperature over night. .The methanol was removed in vacuo i-andcthei aqueous residue iwas-extracted with .ether, and. the ether solution was washed with 2 N hydrochloric acid, then with .10 sodium bicarbonate, and then was dried over sodium sulfate. Evaporationof the ether solution 1 gave. the desired 3,4-.diaminocarbomethoxy 2- -furaributanol.

= Example. 5

- 5.12 of 3,4adiaminocarbethoxy-2rmethyl tfuran-iprepared accordingto- Example 2) were dissolved in -cc.-.ofglacial. acetic acid and were hydrogenated-ratroom-1 temperature. and atmospheric pressureinthe'presencerof apalladiumon .abariumysulfate catalystuntil 2 molszof hydrogen rhad-been absorbed; The: catalyst was removed by -;filtration and-theglacial :aceticacidwas removed -..-in-.-va'cuo. The. residue .was dissolved in=.eth=er. and

'the'ether solution was extracted with 2N hydrochloric acid. The hydrochloric acid extracts were neutralized with 10% sodium bicarbonate and were concentrated to a small volume in vacuo, and the residue was reextracted with ether. The ether solution was dried over sodium sulfate and the ether was removed on the steam bath. The

resulting oil crystallized on standing and the crystals were purified by recrystallization from ether. Cis-3,4-diamino-Z-methyl-tetrahydrofuran .was thus. obtainedin needles which melted at Example 6 The residue was dissolved in ethyl acetate and the ethyl acetate solution was washed with sodium bicarbonate and was dried over sodium sulfate; Evaporation of the ethyl acetate gave an oil which contained the desired 3,4 diaminocarbethoxy-2-tetrahydrofuranpentanol in the cisconfiguration.

CzHsOOCHN C I I 1120 HooH2n-cHzoH 1 i O l .Em r 4.09 g. of -3,4 diaminocarbethoxy-2-furan- Valerie acid piperidide prepared from 3,4-dicarboxy-Z-furan-valeric acid piperidide according to /NH0 0 OCzHs O ,the procedure described in Examples 1 and 2 were dissolved in 100 cc. oi glacial acetic acid and were hydrogenated at room temperature and atmospheric pressure in the presence of a platinum black catalyst until 2 mols of hydrogen had been absorbed. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, andthe ethyl acetate solution was extractedwith sodium bicarbonate, and was dried over sodium sulfate.

Evaporation of the ethyl acetate gave an oil which contained the desired cis 3,4-diaminocarbethoxy- 2-tetrahydrofuran-valeric acid piperidide.

Example 8 10.0 g. of 3,4-diaminocarbomethoxy-2-furanbutanol (prepared according to Example 4) were hydrogenated at room temperature and atmospheric pressure in 400 cc. of glacial acetic acid in the presence of a palladium black catalyst until 2 mols of hydrogen had been absorbed. The catalyst was removed by filtration, the glacial acetic acid was removed in vacuo, and the resulting oil was dissolved in ethyl acetate. The ethyl acetate solution was washed with 10% sodium bicarbonate, was dried over sodium sulfate, and the solvent was removed in vacuo. Distillation of the residue at 180-200 C. at 0.02 mm. gave a colorless oil which contained the desired cis 3,4 diaminooarbometho-xy 2 tetrahydrofuranbutanol.

Example 9 5.0 g. of 3,4-diaminocarbophenoxy-Z-methylfuran (prepared according to Example 3) were dissowed in 200 cc."of glacial. acetic acidxand Example 10 3.32 g. of cis 3,4-diaminocarbethoxy-2-tetrahydrofuranpentanol were. dissolved in 50 cc. of glacial acetic acid, and cc. of a 2% solution of chromic acid in glacial acetic acid were slowly added. The mixture was kept at room temperature for twelve hours and the excess of chromic acid was destroyed by the addition of methanol. The solution was evaporated to dryness in vacuo and the dark green residue was dissolved in water and was extracted with ethyl acetate. The ethyl acetate soluble parts were separated into acid and neutral substances with 2 N sodium carbonate in the usual manner. From the respective acid fraction cis 3,4-diaminocarbethoxy-2-tetrahydrofuranvaleric acid was obtained.

dHaving thus describedKthe invention, what is claimed is:

1. The Z-substituted furancompounds formula RZOOOHN i X,(CH2)=R1 RzOOGHN wherein X is a nucleus selected from the group consisting of the furan and tetrahydrofuran nu cl'ei, the RzOOCl-IN- groups being severally attached in the 3 and l positions of the saidfnucleus and the '(CE2 PR1 group being attached in the 2-position of thesaid nucleus, 3: standsfor one of the integers 1, 2, '3; 4, 5 and 6,R1 stands fora member selected from the group consisting of the of hydrogen, hydroxyl, carboxyl, carboxylic acid ester groups and carboxylic acidamide: "groups, and R2 stands for a member selected from the group consisting of alkyl, aralkyl and aryl.

2. The 2-substituted furan compounds of the formula RzOOCHN NHGOOR:

i l mma-R1 ylic acid amide groups, and R2 stands for a member selected from the group consisting of alkyl, aralkyl and aryl.

3. The Z-substituted tetrahydrofuran compounds of the formula R20 0 CHN\ HCC.

H O BIC-(CH2) :R

wherein at stands for one of the integers 1, 2, 3, 4, 5 and 6, R1 stands for a member selected from the group consisting of hydrogen, hydroxyl, car- NHCOOR:

'7 ibexyleicarboxyl-ic.zacideester roups andecaizboxiyli zacidamide grcupsnandifizzstands for amemhem-selected;ifromzithes roup consisting of lkyl aralkyhand; arr/1.;

.4;; A 13,.4. diaminocarbethox flrfumnpen a Qfh'thfi formula-1 p g H 5;,Al3,4-1-,diaininocarbethoxy-tetrahydro-2efuranpentanol of theformula O2H5OOCHN I NHCOOCQHL .IfzO vHG-2(CHi)4--QH2OH- I The cis-3,4ediami-nocarbethoxy tetrahydroe zefuranpentanol" of. the formula 0211500 GHN' \N HC 0 0 02112 c-- o H j I "H20" 'HC'(CH2)4-CH2OH '7. In a process forthemanu-facture-of ca: biotin analog; thezstep :of subjecting-.a-compound- 01 the formula R20 OGHN- NBC 0011;

melee; thei tep of isubiectine; aiC0mpQ11I1d;.l0f the formula-x :wherein x,.stands=for.oneofitheintegersil, 2; 3, 4; 5; and 56;: and R2 stands for 1 amember selected frcmzthezgroup consisting of alkyl,,aralkylaand ary1 -,:rtonthesactiontof hydrogen in the presence of a hydrogenating catalyst, whereby the =furan ring is converted into a. tetrahydrofuran ring.

9. In a process for the manufacture of a biotin 'analeg,-- the step of subjecting a compoundof the formula .HigQzOOCHN I NHOOOGzHa whereina: stands. for one of theintegers 1, 2, 3,7 4, 5,and 6, to the action of hydrogen in the presence of a .hydrogenating ,catalyst, whereby the. furan ring is converted into a tetrahydrofuran ring.

10.. In a process for the-manufacture ofya biotin analog, the, steptof subjecting a compound of the formula 150.20 0 CHN NHG 0.0 c 2H5 to the action of hydrogenin the presence of a hydrogenating catalyst, whereby the furan ring is converted into a' tetrahydrofuran ring.

K Q'AU TH E NN- EF REN ES T D 'I he fo-llowingmreferences are of record-in the file of "this patent:

U ITEDWSTA ES: PATENTS Number: Name Date .'2;005;538;,=' vEngelmarm June 18; 1935 r 2,231,278? Adams-'etial Feb. 11; 1941 52317 286 Martin' -etgal Apr. '20, 1943 Certificate of Correction Patent No. 2,453,627. November 9, 1948.

KLAUS HOFMANN It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 2, line 45, for the word hydrogenerating read hydrogenating;

and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 22nd day of March, A. D. 1949.

THOMAS F. MURPHY,

Assistant Oommissioner of Patents. 

